N-pyridine 5-aminooxazoles

ABSTRACT

The present invention is concerned with compounds of formula I:   wherein R1 is heteroaryl and R2 is alkyl, aryl, or heteroaryl. Compounds of this invention exhibit central nervous system depressant properties.

[muted States Patent [1113524397 72] inventor Maximilian Von Strandtmann [56] References Cited I A I N 3523 "4- UNITED STATES PATENTS pp o. 7 Filed J y 22,1969 $317,553 5/l967 Crowther et al. ..6()/3()7 [45] Patented Nov. 30, 1971 Primary ExaminerAlan L. Rotman [73] Assignee Warner-Lambert Company Attorneys-Albert H. Graddis, Henry E. Millson, Jr.. Frank S.

M ri Plain NJ, Chow. Neil D. Edwards and Anne M. Kelly [54] N-PYRIDINE S-AMINOOXAZOLES ABSTRACT: The present invention is concerned with com- 4 Claims, No Drawings pounds of formula 52 0.5. CI 260/296 R,

260/256.4 R, 260/287 R, 260/288 R, 260/295 AM, 260/295.5 A, 260/304, 260/306.8 R, 260/307 0 N R, 260/308 R, 260/309.2, 260/558 R, 260/326.l4,

424/263, 424/258, 424/272 I wherein R l is heteroaryl and R is alkyl, aryl, or heteroaryl. 307 Compounds of this invention exhibit central nervous system depressant properties N-PYRlDlNE S-AMINOOXAZOLES The present invention relates to N-heteroaryl S-amino-oxazoles having the following structural formula:

I l I wherein R is heteroaryl and R is lower alkyl, aryl, aralkyl, or heteroaryl.

In the above definitions for R and R the term heteroaryl" encompasses the monocyclic and bicyclic hetero aromatic compounds having at least one hetero atom in the ring which maybe either nitrogen, oxygen or sulfur. Representative heteroaryl radicals falling within this definition are, for example, pyridine, quinoline, pyrrole, indole, thiophene, benzimidazole, tetrazole, pyrymidine and the like. The term ary1" denotes an aromatic radical, preferably of six to carbon atoms, such as for example, phenyl, tolyl and the like. The term aralkyl" encompasses lower alkyl groups in which an aryl group as defined above is substituted for a hydrogen atom, such as for example, benzyl, phenethyl and the like. The term lower alkyl as'used herein includes lower aliphatic hydrocarbons having one to five carbon atoms arranged in a straight carbon chain.

The compounds of this invention are useful in cases where a reduction in skeletal muscle spasm is indicated. For example, at a dose of 200 mg./kg. intraperitoneally in laboratory animals, such as rats, the compounds of this invention produce a reduction in body tone lasting for 24 hours. Simultaneously, the motor activity and temperature are also decreased for a period of about 3 to 6 hours. Generally speaking, a dose range from 100 to 500 mg./kg. is recommended to produce the desired reduction in motor activity. This dosage regimen may, of course, be varied according to body weight, sex, age, species of the mammal being treated as well as the severity of the condition being treated, by methods well known to the healing an.

In order to use these compounds, they are formulated with such standard phannaceutical carriers, such as lactose, mannitol, dicalcium phosphate into dosage forms such as tablets, capsules, and the like. They can also be combined with parenterally acceptable vehicles such as sesame oil, arachis oil and the like to form dosage forms suitable for parenteral injectlon.

According to the present invention, compounds of type 1 are prepared by acylation of heteroarylamines of type 111 with azlactones of type I1 followed by cyclodehydration of the intermediate compounds of type IV. The foregoing reaction is illustrated by the following schematic diagram:

l II III IV in which R, and R, are as previously defined.

Starting compounds III are readily available from commercial sources, for example, Aldrich Chemical Co. Azlactones of type ll were prepared by the procedure described in Organic Syntheses, Vol. 47, p. 101 (John Wiley & 'Sons, lnc., New York, N.Y., 1967):

The followingexamples are included in order further to illustrutethejnvention. 1

EXAMPLE 1 N-[(lndol-2-ylcarbamoyl)methyl]benzamide EXAMPLE 2 N-[ 2-Pyridylcarbamoyl )methyl lbenzamide A solution of 1 g. 2-aminopyridine and 1.75 g. of 2-phenyl- 5-oxazolone in 50 ml. of THF is refluxed for 9 hrs. Concentration to half the original volume and chilling on an ice bath produces crystals, which are recrystallized from ethyl acetate. M.P. 172-l74; Yield: 0.6 g. (21%).

Anal. Calcd. for c,.,n, N,o,: C, 65.87; H, 5.13; N, 16.46. Found: C, 65.85; H, 5.07; N, 16.65.

EXAMPLE 3 N-[ lH-Tetrazol-S-ylcarbamoyl)methyllbenzamide A solution of 1 g. 5-amino-1H-tetrazole, 1.6 g. 2-phenyl-5- oxazolone in 100 ml. THF is refluxed for 5 hrs. Crystals which separate out of the hot solution are filtered off, slurried twice, at 1 hour each, with THE, filtered and dried. M.P. 254256; yield: 2.3 g.

Anal. Calcd. for C H N O C, 48.78; H, 41.09; N, 34.14. Found: C, 48.56; H, 4.15; N, 34.17.

EXAMPLE 4 N-[ 2-Benzothiazo1ylcarbamoyl )methyl benzamide A solution of l g. 2-aminobenzothiazole, 1.08 g. of 2-phenyl-5-oxazolone and 50 ml. THF is refluxed for 7% hrs. The precipitate is filtered off and recrystallized from EtOH (-45O ml./gm.). M.P. 262264; yield: 1.4 g. (70%).

Anal. Calcd. for C H N O,S: C, 61.72; H, 4.21; N, 13.50; 50 m1. THF and refluxing for 6 hrs. The product is recrystal- S, 10.30. Found: C, 61.75; H, 4.31; N, 13.48; S, 10.43. lized from abs. EtOH. M.P. 202-204; yield: 1.1 g. (59.5%).

Anal. Calcd. for C,,,H,-,N O,: C, 70.34; H, 5.58; N, 13.67. EXAMPLE Found: c, 70.14; H, 5.78; N, 13.51.

EXAMPLE 9 d amt -cll,-nll-t z l0 (7 N 0 0 )NH-CCH NH-fi- N l O G N-[ 2-Benzimidazolylcarbamoyl )methyl lbenzamide A solution of 0.5 g. 2-aminobenzimidazo1 and 0.6 g. of 2- N ms'chbmpynd'z'yl)ca'ba'myllmethy'lbenzam'de pheny1-5-oxazolone in 50 ml. of THF is refluxed until a Is prepared in the same manner as N-[(2-pyridy1 carpl'oduct separates out (=30 min.). This is filtered off and bamoyl)methyl]benzamide using 1 g. 2-amino-5-chlopyridine, recrystallized from 95% EtOH. M.P. 303305; yield: 0.9 g. 1.25 g. 2-phenyl-5-0xamlone, in 50 ml. THF and refluxing for (82%). 18 hrs. The product is recrystallized from abs. ethanol. M.P.

Anal. Calcd. for c,,l-l,,N,o,: c, 65.29; H, 4.80; N, 19.04. 229 230"; yield: 1.6 g. (71.5% Found: C, 65.2; H, 4.92; N, 18.99. Anal. Calcd. for c,,ll,,N,o,cl= C, 58.04; H, 4.18; N, 14.50.

Found: C, 57.77; H, 4.16; N, 14.25. EXAMPLE 6 EXAMPLE 10 11 f NH-0-CH,-NH-4 3 O 0 ll .1

N-[( 2-Quinolylcarbamoy1)methyl]benzamide N-[(3-Pyridylcarbamoy1)methyl]benzamide ls prepared in the same manner as N-[(2-pyridy1 car- 18 prepared in the same manner as N-[(2-pyridylcarbamoyl)methyl]benzamide using 1 g. 2-aminoquinoline, 1.1 g. bamoyl)methyl]benzamide using 2 g. of 3-aminopyridine, 3.5 Z-phenyl-S-oxazolone and THF. The product is recrystallized g. of 2-pheynl-5-oxazolone and 50 ml. of THF. The product is from absolute EtOH. M.P. 218219;yie1d: 1.7 g. (81%). recrystallized from acetonitrile. M.P. 193195; yield: 2.3 g.

Anal Calcd. for c,,,ll,,N,,0,. c, 70.80; H, 4.95; N, 13.76. 43% Found: C, 70.98; H, 5.00; N, 13.95. Anal. Calcd. for C,,H,,N,0,: C, 65.87; H, 5.13; N, 16.46.

Found: C, 66.16; H, 5.22, N, 16.50. EXAMPLE 7 EXAMPLE 1 1 N 1 1 I Q NH-C-CH NHC l1 l O 0 5O N-[N-Methylphenylcarbamoyl)methyl]benzamide IS P p in Same manner as 1W y can N-[(2-Pyr1mldlnylcarbamoyl)methyllbenzamlde bamoyl)methy1]benzamide using3 g. N-methylaniline, 4.5 g. ls prepared in the same manner as N-[(2-pyridylcar- 2-phenyl-5-oxazolone in m1. THF and refluxing for 28 hrs. barnoy1)methy1]benzamide using 2 g. of 2-aminopyrimidine, The product is recrystallized from Skelly B. M.P. 84-85; 3.4 g. 2-phenyl-5-oxazolone and 50 ml. THF. The product is yield: 4.7 g. (63%). recrystallized from ethyl acetate. M.P. 219-220; yield: 0.3 g.

Anal. Calcd. for CmHmNgOgZ C, 71.62; H, 6.01; N, 10.44. (55%). Found: C, 71.70; H, 6.02; N, 10.18. Anal. Calcd. for C,;,H,,N,O C, 60.93; H, 4.72; N, 21.87.

Found: C, 60.78; H, 4.74; N, 21.87. EXAMPLE 8 EXAMPLE 12 65 s NH-C-CH NH-C NHCCHry "Q l 1 0 7 CH1 W N N 1 lMethylindol-Z-yl)carbamoyllmethyl lbenzamide N-[(2-Thiazolylcarbamoy1)methyllbenzamide ls prepared in the same manner as N-[(2-indolyl carls prepared in the same manner as N-[(2-pyridyl carbamoy1)methyl]benzamide, using 1.1 g. 1-methyl-2-amino inbamoyl)methyl]benzamide using 1 g. of 2-aminothiazole, 1.6

dole HCl 1 g. 2-phenyl-5-oxazolone, 0.5 g. sodium acetate in g. of 2-phenyl-5-oxazolone and 50 ml. THF refluxing for 4 hrs.

6 The product is recrystallized from abs. EtOH. M.P. 238239, Anal. Calcd. for C H N OS: C, 65.51; H, 3.78; N, 14.32; S, yleldz 8- 10.93. Found: C. 65.55; H, 3.89; N, 14.31; S, ll.l6.

Anal. Calcd. for C H N O S: C, 55.16; H, 4.24; N, 16.08; 5, 12.27. Found: c, 55.32; 11, 4.40; N, 16.29; s, 12.21. EXAMPLE 16 5 EXAMPLE l3 1 19114320 (L J. .1. \N NH- I =(llH 2-[ 2-Phenyl-5-oxazolyl )amine ]thiazole -l( y y l lpy Is prepared in the same manner as 2-[(phenyl-5ox- 5 g. N-[(2-pyridyl carbamoyl)methyl]benzamide is added amlYDammelPyndme 6 f" to 100 g. of PPE and stirred for hrs. The solution is poured bamoylmlethynbenzam'de and 150 "3 i Product onto 300 f ice and water with stirring and basified with recrystalllzed from abs. ethanol. M.P. 190 l9l y1eld: 3.8 g.

ammonium hydroxide. The precipitate is filtered, washed with (635%) water and is recrystallized from abs. ethanol. M.P. l69-170; 25 Anal- Calcd- CIZHQNGOS: C, 59.24; H, 3.73; N, 17.27.

yield; 1,5 (32%), Found: c, 58.95; H, 4.02; N, 17.12; s, 13.07.

Anal. Calcd. for CMHUN3O: C, 70.87; H, 4.67; N, 17.71. Found: c, 70.98; H, 4.7 1; N, 17.80. EXAMPLE EXAMPLE 14 01 N L JNHC=CH ll N 1 1 5 NH-C=CH N I I \I/ H 0 N 5-Chloro-2[(2-phenyl-5-oxazolyl)aminolpyridine 2[(Z-Phenyl-S-oxazolyl)aminelbenzimidazole 4 [S P R f sfame manner as P "y IS P p Sflme manner as -l (1 y carbamoyl)methyllbenzamide and 4.5 g. PPE. The product is azolynammolpyndme 10 Nuzbenz'mldazolylcar' recrystallized from 95% ethanol. M.P. 23 l232; yield: 1.2 g. bamoyl)methyl]benzamide, and 200 gm. PPE. The product is (62%) recrystallized from 95% ethanol. M.P. 238-239; yield: 7.1 g. AnaL Calcd for CHHmNaOCj; C, 139; H, 37 N, 1547;

(70%)- c1, 13.05. Found: c, 62.01; H, 3.72; N, 15.35;c1, 13.05.

Anal. Calcd. for C,6H12N.,O: C, 69.55; H, 4.38; N, 20.28. Found: C,69.6l;H,4.39; N, 20.57. EXAMPLE18 EXAMPLE 15 q s Nil-0:01; J N 1 /NHC===CH N 1 Y.

2-[(Phenyl-S-oxazolyl)amine]quinoline ls prepared in the same manner as 2[(phenyl-5-ox- 7Q azolyl)amine]pyridine using 3.7 g. of N-[(2-quninolyl carls prepared in the same manner as 2-[( he l-5- bamoyl)methyl]benzamide and g. of PPE. The product is azolyl)amino]pyridine using 5 g. N-[(2-benzothiazoylycarrecrystallized from ethyl acetate. M.P. l-l92: yield: 2.7 g. bamoyl)methyl]benzamide and g. of PPE. The product is recrystallized from abs. ethanol. M.P. 228 229; yield: 3 g. Anal. Calcd. for C H N O: C, 75.24; H, 4.56; N, 14.63. (60%). 1 75 FoundzC, 75.15; H,4.'56; N, 14.60.

2[(2-Phenyl-5-oxazolyl)amine]benzothiazole EXAMPLE 19 NHo=oH 3-[(2-phenyl-5-oxazoly1)aminolpyridine ls prepared in the same manner as 2-[(phenyl-5-oxazoly1)amino]pyridine using 1 g. of N-[(3-pyridyl carbamoyl)methyl]benzamide, 25 g. PPE and stirring for 72 hrs. The product is recrystallized from toluene. M.P. l48-l50; yield: 0.5 g. (49%).

Anal. Calcd. for C H N O: C, 70.87; H, 4.67; N, 17.71. Found: C, 70.89; H, 4.76; N, 17.57.

EXAMPLE 2O H o N 2-[(2-Phenyl-5-oxazolyl)amino]indole 4.5 g. of N-[(indol-2-yl carbamoyl)methyl]benzamide is stirred with 90 g. PPE for 45 hrs. The solution is poured onto ==300 ml. of ice and water with stirring and basified with ammonium hydroxide. The precipitate is filtered off and washed well with water. Yield: 3.8 g. (94%). The product is recrystallized from acetonitrile. M.P. 238240; yield: 1.6 g. (39.5%).

Anal. Calcd. for c,,H,,,N,0: C, 74.16; H, 4.73; N, 15.26.

Found: C, 74.11;H, 5.95; N, 15.05.

EXAMPLE 21 NHC:2-C1I \N/ l 1 l-Methyl-2-[(phenyl-S-oxazolyl )aminolindole R HN whereinR is pyridine or chloropyridine and R is lower alkyl or phenyl.

2. A compound according to claim 1 which is 2-[(phenyl-5- oxazolyl)amino]pyridine.

3. A compound according to claim 1 which is 5-chloro-2-l (2pheny1-5-oxazolyl)amino]pyridine.

4. A compound according to claim 1 which is 3-[(2-phenyl- 5-oxazolyl)amino]pyridine. 

2. A compound according to claim 1 which is 2-((phenyl-5-oxazolyl)amino)pyridine.
 3. A compound according to claim 1 which is 5-chloro-2-((2-phenyl-5-oxazolyl)amino)pyridine.
 4. A compound according to claim 1 which is 3-((2-phenyl-5-oxazolyl)amino)pyridine. 